The present invention is concerned with a novel process for the catalytic oxidation of compounds containing an allylic group using ruthenium based catalysts. The process is generally useful for the oxidation of compounds containing allylic hydrogens or alcohols, and particularly for xcex94-5 steroidal compounds.
The principal mediator of androgenic activity in some target organs, e.g. the prostate, is 5xcex1-dihydrotestosterone (xe2x80x9cDHTxe2x80x9d), formed locally in the target organ by the action of 5xcex1-reductase, which converts testosterone to DHT. Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone (xe2x80x9cTxe2x80x9d) or similar androgenic hormones in the metabolic system. Inhibitors of 5xcex1-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially U.S. Pat. No. 4,377,584, issued Mar. 22, 1983, and U.S. Pat. No. 4,760,071, issued Jul. 26, 1988, both assigned to Merck and Co., Inc. It is now known that a second 5xcex1-reductase isozyme exists, which interacts with skin tissues, especially in scalp tissues. See, e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791 (November 1992). The isozyme that principally interacts in skin tissues is conventionally designated as 5xcex1-reductase 1 (or 5xcex1-reductase type 1), while the isozyme that principally interacts within the prostatic tissues is designated as 5xcex1-reductase 2 (or 5xcex1-reductase type 2).
The oxidation of xcex94-5-steroidal alkenes to the corresponding enones is an important step in the synthesis of steroid end-products useful as 5xcex1-reductase inhibitors. Chromium based oxidations have previously been used for the oxidation of allylic groups, but are environmentally unacceptable and require silica gel chromatography. The instant invention provides an improved alternative method for oxidizing xcex94-5-steroidal alkenes, which is convenient to run, and is environmentally friendly. Furthermore, the yield and purity of the oxidized intermediate obtained by the instant process meets or exceeds those obtained when other previously known oxidation methods are used.
The novel process of this invention involves the oxidation of compounds containing an allylic alcohol group or allylic hydrogens to the corresponding enones using a ruthenium based catalyst in the presence of a hydroperoxide. Particularly, this invention involves conversion of xcex94-5-steroidal alkenes to xcex94-5-7-keto-steroidal alkenes, using a ruthenium based catalyst in the presence of a hydroperoxide. This novel process can be exemplified in the following embodiment: 
Compounds of Formula II are useful as intermediates in the preparation of 7xcex2-substituted 3-keto-4-azasteroid compounds, such as those which are 5xcex1-reductase inhibitors. 5xcex1-Reductase inhibitors are useful in the treatment of hyperandrogenic disorders such as benign prostatic hyperplasia, acne vulgaris, seborrhea, female hirsutism, androgenic alopecia, male pattern baldness, and the prevention and treatment of prostatic carcinoma.
The novel process of this invention involves the discovery that steroidal compounds containing a C5-C6 double bond (i.e., xcex94-5-steriodal alkenes) can be oxidized to the corresponding 7-keto compounds by treatment with a hydroperoxide in the presence of a ruthenium-based catalyst. Using the same process, compounds containing an allylic alcohol group can likewise be oxidized to their corresponding ketones. For reference, the standard numbering around the unsubstituted core steroid structure and the letter designation of the rings is as follows: 
It has surprisingly been discovered that the instant oxidation process will proceed using any catalyst which is ruthenium based. Many ruthenium based catalysts are known in the art, and any such ruthenium based catalyst can be used with the instant process. Examples of ruthenium based catalysts that may be used in this process include but are not limited to the following: RuW11O39SiNa5, RuCl3, RuCl2(PPh3)3, Ru(acac)3, Ru(dimethylglyoximato)2(PPh3)2, RuO2, Ru(TPP)(CO)(THF), Ru(bipy)2Cl2, Ru(TPP)(CO)(THF), Ru/C and K5SiRu(H2O)W11O39. xe2x80x9cTPPxe2x80x9d is tetraphenylporphine; xe2x80x9cacacxe2x80x9d is acetylacetonate; xe2x80x9cbipyxe2x80x9d is bipyridine. Ruthenium based catalysts are described in, e.g., R. Neuman, J. Am. Chem. Soc., Vol. 112, 6025 (1990); S-I. Murahashi, Tetrahedron Letters, Vol. 34, 1299 (1993).
Particularly, a ruthenium sodium tungstate-based catalyst is used, and more particularly RuW11O39SiNa5. A catalytic amount of the ruthenium compound is used in this reaction. Those skilled in the art are familiar with the use of catalytic amounts of reaction catalysts, and will appreciate that the amount of catalyst that can be used may vary with the scale of the reaction and the particular ruthenium based catalyst employed. An exemplary amount of the ruthenium based catalyst ranges from about 0.05 to 5 mol %, and particularly about 0.5 mol % of catalyst per mole % of starting material, but variations beyond this range would be acceptable as well.
The alkene starting material is treated with a hydroperoxide in the presence of the ruthenium-based catalyst for conversion to the corresponding enone. Many hydroperoxides are known in the art, and any such hydroperoxide can be used with the instant process. Examples of hydroperoxides that may be used in this process include but are not limited to t-butyl hydrogen peroxide (t-BuOOH), cumene hydroperoxide, hydrogen peroxide, and benzoyl peroxide, with t-BuOOH being preferred. An amount of hydroperoxide sufficient to complete the oxidation should be used, for example at least about 2 moles, and preferably about 8 to 10 moles per mole of starting material.
Any commercially available solvent or combinations thereof may be employed in the instant process step, such as alkanes, ethers, alcohols, halogenated solvents, water, etc. Examples of the variety of solvents that may be used include but are not limited to toluene, ethyl acetate, hexane, chlorobenzene, heptane, t-butyl methyl ether (MTBE), benzene, acetonitrile, cyclohexane, methylene chloride, 1,2-dichloroethane and t-butyl alcohol (t-BuOH), or a combination thereof. When using RuW11O39SiNa5 as the catalyst, heptane is the preferred solvent. With RuCl2(PPh3)3, chlorobenzene or benzene are preferred solvents.
This oxidation process may be run at a temperature between about xe2x88x9220xc2x0 C. and up to the reflux temperature of the solvent used, for example about 100xc2x0 C., and particularly between about 5xc2x0 C. and 50xc2x0 C., and more particularly at about 15xc2x0 C. The reaction may be run at any pH, and particularly at an acidic pH, and more particularly at a pH of about 1. The pH of the reaction mixture may be adjusted prior to addition of t-BuOOH by addition of an aqueous acid such as sulfuric acid. Although not required, the reaction is preferably run under an inert atmosphere, such as nitrogen or argon.
xcex94-5-Steroidal alkenes that can be used in this process are known in the art. For example, see those listed and available through the Sigma Chemical Co.
One embodiment of the present invention comprises the step of treating a compound of Formula I 
with a hydroperoxide in the presence of a ruthenium based catalyst in a solvent to form a compound of Formula II 
wherein Y is hydroxy, an esterified hydroxy group, keto or ethylene ketal, X is xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(CH3)xe2x80x94 or xe2x80x94N-2,4-dimethoxybenzyl, and Z is 
The oxidation reaction is not affected by the substituent at the 16- or 17-position of the steroid, and thus xe2x80x9cAxe2x80x9d can be any synthetically feasible substituent. The flexibility and broad applicability of the instant process is demonstrated by the fact that it is not limited by the choice of substituent at the 16- and 17-positions of the steroidal starting material.
Representative examples of xe2x80x9cAxe2x80x9d include but are not limited to: xe2x80x94H; keto (xe2x95x90O); protected hydroxy, e.g. dimethyl-t-butyl silyloxy, trimethylsilyloxy, tri-ethylsilyloxy, tri-i-propylsilyloxy, triphenylsilyloxy; acetate; hydroxy; protected amino, e.g. acetylamino; amino; C1-10 alkyl, e.g. methyl, ethyl, 1,5-dimethylhexyl, 6-methylhept-2-yl cholestanyl 17-side chain, pregnane or stigmasterol 17-side chain; aryl substituted C1-10 alkyl, e.g. omega-phenylpropyl, 1-(chlorophenoxy)ethyl; aryl carbamoyl substituted C1-10 alkyl, e.g. 2-(4-pyridinyl-carbamoyl)ethyl; C1-10alkylcarbonyl, e.g. isobutylcarbonyl; arylcarbonyl, e.g. phenylcarbonyl; ether-substituted C1-10alkyl, e.g. 1-methoxy-ethyl, 1-ethoxy-ethyl; keto-substituted C1-10alkyl, e.g. 1-keto-ethyl; heteroaryl-substituted C1-10 alkyl, e.g. omega-(4-pyridyl)-butyl; carboxy; carboxylic esters, e.g. C1-10 alkylcarboxylic esters such as carbomethoxy; carboxamides, e.g. C1-10 alkylcarboxamides or aralkylcarboxamides such as N,N-diisopropyl carboxamide, n-t-butyl carboxamide or N-(diphenylmethyl)-carboxamide; carbamates such as C1-10 alkylcarbamates, especially t-butylcarbamate; substituted or unsubstituted anilide derivatives wherein the phenyl may be substituted with 1 to 2 substitutents selected from ethyl, methyl, trifluoromethyl or halo (F, Cl, Br, I); ureas, e.g. C1-10 alkylcarbonylamino ureas such as t-butylcarbonylamino urea; C1-10 alkylcarbonylamino, e.g. t-butylcarbonylamino; ethers, e.g. n-butyloxy, ethylene ketal; substituted and unsubstituted aryl ethers such as chlorophenyloxy, methylphenyloxy, phenyloxy, methylsulfonylphenyloxy, pyrimidinyloxy; and the like.
The term xe2x80x9calkylxe2x80x9d includes both straight and branched chain alkyl groups, and xe2x80x9carylxe2x80x9d includes phenyl, pyridinyl and pyrimidinyl.
Hydroxy and amino protecting groups are known to those of ordinary skill in the art, and any such groups may be used. For example, acetate, benzoate, ether and silyl protecting groups are suitable hydroxy protecting groups. Standard silyl protecting groups have the general formula xe2x80x94Si(Xa)3, wherein each Xa group is independently an alkyl or aryl group, and include, e.g. trimethylsilyl, tri-ethylsilyl, tri-i-propylsilyl, triphenylsilyl as well as t-butyl-di-(Xb)-silyl where Xb is methyl, ethyl, i-propyl or phenyl (Ph). Standard amino protecting groups have the general formula xe2x80x94C(O)-Xc, wherein Xc is alkyl, aryl, O-alkyl or O-aryl, and include, e.g. N-t-butoxycarbonyl. See also Protective Groups in Organic Synthesis, T. W. Green et al. (John Wiley and Sons, 1991) for descriptions of protecting groups.
As will be appreciated by those of ordinary skill in the art, when Y is an esterified hydroxy group, substituents such as those of Formula III are intended 
wherein Xd can form any synthetically feasible ester group. The process is not limited by the choice of any particular ester form for Y. Representative examples of Xa include but are not limited to straight or branched chain alkyl, e.g. C1-18 alkyl, phenyl, mono- or di-substituted phenyl wherein the substituents include, e.g., halogen, alkoxy, and amino.
The intermediate compound II is useful for making 7xcex2-substituted 4-azasteroid compounds, and particularly those which are inhibitors of 5xcex1-reductase. Examples of such compounds include but are not limited to those disclosed in U.S. Pat. Nos. 4,377,584 and 4,760,071; WO 93/23419; and WO 93/23420. More particularly, compounds that can be made from intermediate II include those of general Formula IV: 
wherein R is H or methyl, Z is 
and Alk is selected from C1-25 linear or branched alkyl, e.g., methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), n-butyl (n-Bu), sec-butyl, isobutyl, tert-butyl (t-Bu) and the like; C3-6 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and allyl. Processes for making such compounds are taught for example in U.S. Pat. No. 5,237,064, WO 93/23419 and WO 93/23420 and PCT application having the Ser. No. 94/12071.
A further exemplary synthetic scheme showing how to make compounds of Formula IV is as follows: 
The starting materials for the process generally are the 3-acetoxy-androst-5-enes which are known and available in the art.
Z is 
The term xe2x80x9cAxe2x80x9d is described above and can be any substituent preferably inert and non-interfering under the particular reaction conditions of each step outlined in the above reaction scheme.
The A group can also be a protected hydroxy or protected amino group which undergoes the indicated reaction sequence and then is subsequently removed, or it can also be removed during a particular step providing it does not interfere with the indicated reaction. For example, where A is xe2x80x94O-TBDMS, i.e., t-butyldimethylsilyloxy, the silyl protecting group can be removed during e.g., the ring closure step of the seco acid 6 to the 4-aza steroid 7, such that the subsequent steps are performed on the 16- or 17-OH compound. Also, the starting A group can be a precursor to the finally desired A group and be converted thereto concurrently in one of the steps. For example, where A contains a double bond, e.g., a stigmasterol analog, the double bond in the 16- or 17-side chain may also be oxidized during the seco acid formation in going from 5 to 6.
As shown in the above Reaction Scheme, the xe2x80x9cAlkxe2x80x9d substituent can be introduced onto the B ring of the 4-aza steroid generally by the application of an organometallic carbonyl addition reaction, e.g., the Grignard reaction in which the 7-carbonyl group can be reacted with the Grignard reagent containing xe2x80x9cAlkxe2x80x9d as the R radical in RMgX. The Grignard reaction conditions are conventional and include the use of, e.g., methyl, allyl or cycloalkyl magnesium chloride, ethyl magnesium bromide, cyclopropyl magnesium bromide, and the like. Preferably, the Grignard reagent is used with CeCl3. Usable dry solvents include, e.g., tetrahydrofuran (THF), diethyl ether, dimethoxyethane, and di-n-butyl ether. The reaction is conducted under dry conditions generally in the temperature range of 0xc2x0 C. to 40xc2x0 C. Generally, the reaction requires about 6 to 24 hours for completion. Other organometallic carbonyl addition reactions can be used in this step, such as those utilizing lithium and zinc organometallic reagents which are known in the art.
The adduct 3 is then oxidized with e.g. aluminum isopropoxide and cyclohexanone (Oppenauer oxidation conditions) in e.g. refluxing toluene solvent to produce the 7-alkyl-4,6-dien-3-one 4. Other reagents which can be used are, e.g., aluminum ethoxide or aluminum t-butoxide. Other solvents which can be used include, e.g., methylethylketone (MEK) and xylene. The temperature is generally in the range of about 60 to 120xc2x0 C., and the reaction is carried out under anhydrous conditions and generally requires about 2 to 24 hours for completion.
The dien-3-one 4 is next converted to the 4-ene 5 by treatment with Pd on carbon, DBU, and cyclohexene in a solvent such as ethanol.
The A Ring is next cleaved by treatment with e.g. potassium permanganate, sodium periodate in e.g., t-butylalcohol at 80xc2x0 C. to produce the corresponding seco-acid 6. Other oxidation reagents which can be used include ruthenium tetraoxide and ozone. Other solvents which can be used are: CH3CN, CCl4, methanol (MeOH) and CH2Cl2. The reaction generally requires about 2 to 4 hours to proceed to completion.
The seco-acid in a C2-4 alkanoic acid such as acetic acid (HOAc) is treated with ammonium acetate at about 15-30xc2x0 C. followed by warming to reflux for about 2 to 4 hours. After cooling to about 50-70xc2x0 C., water is added and the mixture seeded to cause crystallization of the ene-lactam 7.
Hydrogenation of the ene-lactam is accomplished with a noble metal catalyst, such as a Pd(OH)2, PtO2, Pd on carbon, Rh on carbon or Rh/Al2O3, and preferably using Rh on carbon or Rh/Al2O3, in a C2-4 alkanoic acid, such as acetic acid, or an alcohol such as ethanol, or ethyl acetate, at about 50-70 psi hydrogen. The reaction is run at about 15-25xc2x0 C. for about 8 to 12 hours, and then the temperature may be raised, e.g., to about 50-70xc2x0 C., until the reaction is essentially complete. The catalyst is removed by filtration and the filtrate is concentrated to dryness. The product 8 may then be purified, e.g., by recrystallization.
The last step, N-methylation, is accomplished by treating a solution of the lactam 8 in an aromatic solvent such as benzene or toluene, in the presence of tetrabutylammonium hydrogensulfate and aqueous alkali such as potassium hydroxide or sodium hydroxide, with methyl chloride gas with rapid stirring at about 40-60xc2x0 C. until the reaction is essentially complete, usually in about 20-30 hours.